The direct delivery of agents to specific target regions of the brain is emerging as an essential tool in the treatment of cancers, neurodegenerative conditions, and other pathologies of the central nervous system. Convention-enhanced delivery (CED) is a preferred method of delivering agents to selected regions of the central nervous system, especially the brain. In CED, a cannula is inserted into the target organ, and aided by direct radiographic visualization, the tip of the cannula is placed in the target structure, such as a specific anatomical feature or tumor. Therapeutic agents such as viral vectors, growth factors, or chemotherapeutic agents are then dispensed from the tip of the cannula at a sufficient rate (for example, 0.2-100 μL/min) to induce a pressurized bulk flow and efficient distribution of the agent by convective flow.
A significant problem in CED is the tendency of the delivered solution to backflow along the cannula track. To address this problem, “stepped” cannulas were developed. The step is an abrupt reduction in diameter between the proximal region of the cannula body and the distal end (from which the agent solution is dispensed). Typically, the step is a face or surface perpendicular to the long axis of the cannula which surrounds the diameter or perimeter of the cannula. Cannula designs having a major step and a minor step, for example, as depicted in FIG. 1, may be used. Advantageously, it was discovered that the step creates a backstop which blocks backflow of infused solution and promotes the even distribution of the agent throughout the target area. Exemplary stepped cannulas are described in United States Patent Application Publication Number 2013/0079748, entitled “Stepped Cannula,” by Bankiewicz et al.,
In CED, localized delivery of the agent, confined within the target region, is essential. Often, the delivered agent is selectively beneficial, being therapeutic within the target region but having a detrimental effect on other regions of the brain. Off-target delivery of agents is wasteful at best, and at worst can result in substantial, negative side effects. For example, a chemotherapeutic agent delivered to a tumor is desirable, but it is undesirable that the chemotherapeutic agent be distributed beyond the region of the tumor.
In practice, it is difficult to select an appropriately sized cannula which will achieve the ideal spacing between the dispensing tip and the step. Once the cannula is inserted into the target area, the operator may observe that the distance between the dispensing tip and major step is too long, as in FIG. 2A. In such case, in order to keep the dispensing tip centered in the target structure, the major step is located outside of the target structure, and the backflow of dispensed solution to the step results in solution being delivered outside of the target structure. Alternatively, the distance between the dispensing tip and the major step may be too short, as in FIG. 2B. When the distance between the step and dispensing tip is too long or too short, the major step cannot be placed at the boundary or opening of the target region while simultaneously placing the dispensing tip within the middle of the target region for optimal delivery. Accordingly, there is a need in the art for CED systems which allow for precise delivery of agents to a target region.
The cannula designs and associated methods disclosed herein provide the art with new cannulas and methods of use which allow for accurate delivery of therapeutic solutions to target regions in the brain or other structures. The novel cannula designs of the invention are adjustable, allowing for placement of the step in the optimal position to minimize off-target delivery.